title: Immediate-early gene expression in structures outside the basal ganglia is associated to l-DOPA-induced dyskinesia.
abstract: Long-term l-3,4-dihydroxyphenylalanine (l-DOPA) treatment in Parkinson's disease (PD) leads to l-DOPA-induced dyskinesia (LID), a condition thought to primarily involve the dopamine D1 receptor-expressing striatal medium spiny neurons. Activation of the D1 receptor results in increased expression of several molecular markers, in particular the members of the immediate-early gene (IEG) family, a class of genes rapidly transcribed in response to an external stimulus. However, several dopaminoceptive structures in the brain that are likely to be affected by the exogenously produced DA have received little attention although they might play a key role in mediating those l-DOPA-induced abnormal behaviours. ΔFosB, ARC, FRA2 and Zif268 IEGs expression patterns were thus characterised, using unbiased stereological methods, in the whole brain of dyskinetic and non-dyskinetic rats to identify brain nuclei displaying a transcriptional response specifically related to LID. Within the basal ganglia, the striatum and the substantia nigra pars reticulata showed an increased expression of all four IEGs in dyskinetic compared to non-dyskinetic rats. Outside the basal ganglia, there was a striking increased expression of the four IEGs in the motor cortex, the bed nucleus of the stria terminalis, the dorsal hippocampus, the pontine nuclei, the cuneiform nucleus and the pedunculopontine nuclei. Moreover, the zona incerta and the lateral habenula displayed an overexpression of ΔFosB, ARC and Zif268. Among these structures, the IEG expression in the striatum, the bed nucleus of the stria terminalis, the lateral habenula, the pontine nuclei and the cuneiform nucleus correlate with LID severity. These results illustrate a global transcriptional response to a dyskinetic state in the whole brain suggesting the possible involvement of these structures in LID.
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
authors.forename: Matthieu F
authors.initials: MF
authors.lastname: Bastide
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dovero
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
authors.forename: Giselle
authors.initials: G
authors.lastname: Charron
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Porras
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Gross
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France. Electronic address: erwan.bezard@u-bordeaux2.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bézard
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001479:Basal Ganglia / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D051921:Fos-Related Antigen-2 / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000978:Antiparkinson Agents; D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D051921:Fos-Related Antigen-2; C483820:Fosb protein, rat; C497874:Fosl2 protein, rat; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C092069:activity regulated cytoskeletal-associated protein; D007980:Levodopa
keywords: Dyskinesia; IEG; Stereology; Whole brain; l-DOPA